New 'Smart Pill' Raises Ethical Questions

NYU bioethicist Arthur Caplansays he can imagine a judge using Proteus to enforce medication as part of a sentence: miss a pill, and your parole is revoked. "The temptation in the legal system to say, 'I can monitor you and make sure you're not a threat' is going to be huge," Caplan says. "Maybe that's good, maybe it's bad, but it's a different world than saying I consent to taking these pills." Those court orders are rare at the moment, since there’s no way to ensure a patient is taking medication outside of a controlled treatment facility — but as pill-tracking becomes easier, those measures could become much more common.

Opinion

November 15, 2017

Where does patient adherence technology go in a post smart-pill era?

Yesterday’s press release about Proteus’ $450 Million digital smart pill approval made the major papers.

WSJ and NYT both offered in depth analysis of technology and user experience challenges. CNN, later in the day, noted that neither Proteus nor Otsuka were willing to comment. Oracle, who hosts the data platform, wasn’t even mentioned.

Interestingly, both original Big Pharma investors and sponsors of this technology are holding back, with neither Novartis nor Otsuka in a hurry to launch any drugs (not even the newly approved Smart Pill version of Abilify - https://www.abilify.com). The patient target group chosen to put through the FDA approval process (Schizophrenia) always seemed like an unfortunate choice.

The negative criticism was entirely predictable and isn’t surprising, because of a variety of factors:

User concern with data security. I don’t know a single person who is keen on swallowing a computer chip and wear a monitoring receiver on their body 24/7. Electronic ankle bracelet anyone? Proteus’ response to this makes no sense “the device stays inside the body and the data is stored in the patch”. Yes, my credit card stays in my wallet, too. But it’s of no use until I take it out to pay for something. The smart pill data has to go somewhere, and if it just stays inside the patient’s body, then there is no point having it at all.

Proteus states that the chip contains no more Silicon (Si) than a banana. That’s fine, perhaps, but who eats up to 3 or 4 bananas a day? Si is not completely inert, and even if it’s a trace mineral used by the body, too much of a good thing can be bad. The banana analogy is alarming, at best. According to WebMd it could contribute to kidney stones, and its safety as a medicinal compound is unknown. It advises pregnant and breast feeding women to avoid intake of supplemental Si.

Proteus attempts to address non adherent (forgetful) patients. But it uses a very big hammer to hit a small mosquito by requiring a) a patient to wear a patch in the correct location, b) to make sure the patch is connected to their smartphone via Bluetooth, c) to make sure the smartphone is within reach and also connected to internet via WIFI or 3G/LTE link, d) to swallow the smart pill and not be concerned if there is no confirmation of the pill having been ingested for up to two hours, or indeed perhaps not being detected at all. So we are targeting poorly adherent patients with an overwhelming technology burden. That’s the opposite of smart. The biggest technology hurdle here is the battery running out of juice. And it warns that the ingestion event might not even be detected by that patch at all.

Tolerance of the patch. The patch is just like any other medical patch (pain or birthcontrol patches, for instance). A good proportion of the population experiences contact dermatitis. Proteus’ instructions are to change location of the patch each week when starting a new one. How many weeks would a patient put up with this? That’s a question that likely has been answered anyway: not too long. One of the main issues of adherence drop off is persistence, meaning patients stop being adherent after some time. The patch seems to just aggravate this issue, not solve it.

It doesn’t do what it is designed to do. Proteus’ smart pill does NOT address the intended purpose of the technology which is to improve adherence. Indeed, the FDA has directed Proteus to specifically say so on their device label. The fact is, adherence measurement does not equal adherence improvement; unless the measurement data are used in a specific way to coach patients about their adherence pattern.

Nobody has addressed cost, but there is a requirement to re-apply for a drug application each time a Proteus smart chip is combined with an existing drug. This costs time and money. In clinical trials, where adherence is of paramount significance, the combination of chip and pill might cause unacceptable delays and possibly then force the drug company to go to market with a chip inside every pill whether they want to or not. This would explain why no actual clinical trial seems to have included this chip in its research protocol. Clinical research involves careful study of side effects. Adding guaranteed side effects by using medical adhesive for the detection patch does not help matters.

There have been effective adherence measurement devices in the market for 30 years. MEMS by Aardex is a smart cap for medicine bottles and has been used in hundreds of studies. eCAP by Information Mediary Corp. is a similar, more modern version of this, and has been in use for over 10 years. Med-ic, also by Information Mediary Corp., is a smart chip inserted in medication packaging to record and transmit medication event histories. In all cases where the chip is part of the packaging, rather than inserted into the actual medication, FDA does not require complicated, lengthy and expensive approvals. The technology has been used by hundreds of thousands of patients over more than two decades. It is robust, affordable and easy to deploy.

What makes package-based adherence monitoring the sensible choice for researchers and clinicians alike is the fact that it can be innocuous to the patient. The patient has to do absolutely nothing, except to take their medicine as usual. The argument of the smart-pill advocates that removal of medication does not prove ingestion is correct. However, it has been shown to be highly correlated.

What is required to drive adherence measurement technologies forward is user adoption. Some pharma and clinical trials teams have waited for the magic smart pill in favor of adopting simpler smart packaging devices. Now that day of reckoning has arrived with Proteus’ FDA approval. The magic has been exposed as just an expensive technology play.

Again, the basic premise that adherence measurement does not in and by itself lead to adherence improvements means that pharmaceutical brand and research teams need to get back to basics. Yes, collect adherence data, but then use it diligently to shape and apply adherence coaching and patient management strategies.

Perhaps to Novartis and Otsuka, their investments in Proteus amount to rounding errors, but instead of a smart pill, they swallowed a bitter one. Oracle has been keeping a very low profile, despite being an early investor. Yesterday was their Juicero moment perhaps.

One positive outcome is for certain - the Proteus experiment has brought the importance of patient adherence to the forefront of discussion once again. Luckily, sensible technologies already exist to collect adherence data, in the form of smart packaging from leading vendors such as Aardex (Westrock) and Information Mediary Corp.

Michael Petersen is co-founder and C.O.O. of Information Mediary Corporation, which has been developing and deploying smart packaging technology since 2001. Over 1.5 Million devices have been sold to-date including over 1 Million smart blister packages used in pharmaceutical clinical trials. Michael is an advocate of sensible technology deployment, and has been a vocal critic of previous technology hypes in the RFID and smart packaging space. He can be contacted at This email address is being protected from spambots. You need JavaScript enabled to view it.

Non Adherence: The Elephant in the Room

by Allan Wilson, MD PhD

If Hippocrates1 knew that patients are non-compliant with their treatment and nearly every clinician since would agree, why does the “elephant in the room” continue to be ignored?

A clinical trial is simply an exercise in optimizing a signal-to-noise ratio. The signal is the desired clinical effect;the noise everything else that obscures the signal. Poor patient compliance is a major source of noise that can now be measured and controlled to increase the accuracy of a trial.

Drugs don’t work in patients who don’t take them. - C.Everett Koop, Surgeon-General

Why are trials not all monitoring compliance, as suggested by Bradley Efron in 1998? The short answer is that trial planners focus on the initial cost of electronic compliance monitors (ECMs) such as IMC’s Med-ic® and Proteus’ Discover®and overlook the tremendous ROI they provide by accelerating trial fulfillment.

At some point, perhaps not in the far future,it will seem as wrong to run a clinical trial without compliance measurement as without randomization. - B. Efron, Statistics In Medicine, 1998(17), 249.

Compliance data are even more important for adaptive trials due to the increased number of decision points increasing the probability of a Type I error, and the smaller signals’ vulnerability to being obscured by noncompliance (and other) sources of noise.

Pray, Mister Babbage, if you put the wrong figures into the machine, will the right answers come out? - Charles Babbage, Polymath, 1864

In addition to providing more accurate data, ECM is a powerful tool for monitoring subjects’ medication-taking behaviour during a clinical trial and providing data to increase the power of the design. This results in cost savings due to the ability of smaller sample sizes to show statistical significance (drug effectiveness) and earlier regulatory approval with longer time on patent protection. With a well-designed blister package equipped with an electronic compliance monitor and good subject education, poor patient compliance can be changed from a liability to an asset with enormous return on investment.

[1] Hippocrates of Cos, Decorum, XIV

Compliance data are used in a number of ways:

To screen patients for compliance characteristics prior to enrolling them in a trial.

To motivate subjects to be more compliant as they progress through a trial. It can be shown that increasing compliance by x% allows for a reduction of the trial’s N by 2x% without changing the study’s power. Fewer subjects means faster regulatory approval and longer patent protection. Hence the large ROI.

To assess subjects’ compliance post hoc. Data mining can throw light on many aspects of subject behaviour and can be tailored to the interests of the sponsor. In one trial it was found that 40 percent of subjects deblistered their medication, something that would have otherwise gone undetected. The problem was solved by developing a more user-friendly format. Another trial showed no significant difference between treatment groups by the primary outcome analyses. The subjects were stratified post hoc according to their compliance and the drug was highly effective for those subjects who actually took it as prescribed.

ECM can serve as a REMS (Risk Estimation and Mitigation Strategy) for trials where noncompliance can have more serious consequences than those associated with simple data inaccuracy. Opioids, for example,can result in fatal overdose when taken to excess, and these drugs are often diverted for sale on the street. ECM detects the deblistering that might suggest such activities and allows the investigator to intervene.

ECM can detect subtle medication-related bias effects that can lead to erroneous conclusions about drug efficacy. And which would otherwise go undetected.

New Research Paradigm:

Apple’s Tim Cook wants to stand Clinical Research on its head and, if anyone can disrupt Clinical Research, it is probably Apple. Med-ic smart blisters give the research team instant access to patient adherence data and the ability to coach patients to be compliant with their medication. The old argument about not wanting clinical trial subjects to be more compliant than those patients who will eventually use the medication in the real world is now officially relegated to the dustbin. Post hoc data “clean up” will one day soon be as irrelevant as dialling a rotary phone. Some Big Pharma research teams are already embracing compliance data; others are ready to jump in. Soon, clinical research will not be defensible without smart blisters, compliance data and full visibility. See www.med-ic.com for details.

eCAP™ is an extension of the Med-ic® smart package concept to the medication vial. In conjunction with Rexam, a global leader in the design and manufacturing of pharmacy vials, IMC's eCAP provides a flexible, dynamic, reliable and cost-effective compliance solution.

IAP Labs is a division of Information Mediary Corporation and was formerly known as XINK Laboratories Ltd., which was acquired by Henkel (ex- National Starch) on June 1, 2006. IAP Labs is dedicated to the development of intelligent and active packaging technologies. IAP Labs Inc. provides development, prototyping, testing, and production of intelligent packaging, printed electronics, printed sensors, and pharmaceutical smart labels from its Ottawa-based facilities (IAPLabs.com).

IAP, eCAP, eCAP/Secure, and "Revolutionize Your Cold Chain" are trademarks of Intelligent Devices Incorporated and are used under license. XINK and InstaCure are trademarks of Acheson.
ECM, Log-ic, CertiScan, Med-ic and "Rx for the Third Millennium" are registered trademarks of Intelligent Devices Incorporated and are used Under license.